JP7011237B2 - Method for manufacturing polymer-impregnated base resin - Google Patents

Description

The present invention relates to a method for producing a polymer-impregnated base resin.

Medical / medical substrates, filters, channels, tubes, etc. used in the medical / medical field are caused by contact with blood inside and outside the body during use, and blood cells such as platelets and proteins are on their surface. Adhesively and adsorbs, and there is a problem that the original function is impaired.

On the other hand, Patent Documents 1 and 2 propose a technique for coating a polymer obtained by polymerizing a hydrophilic monomer on a medical / medical substrate, a filter, a flow path, and a tube surface, but it is also desired to provide other techniques. There is.

Japanese Patent Publication No. 2005-516736 Special Table 2005-523981

An object of the present invention is to solve the above-mentioned problems and to provide a method for producing an excellent protein and a polymer-impregnated base resin capable of imparting low adsorption of blood cells such as platelets.

The present invention relates to a method for producing a polymer-impregnated base resin, which comprises a step of impregnating a base resin with a polymer solution using a solvent having swelling property for the base resin.

The production method preferably involves removing the solvent of the polymer solution after impregnation and then washing with the solvent used for the polymer solution.

The polymer is at least one selected from the group consisting of polyacrylic acid, polyacrylic acid ester, polymethacrylic acid, polymethacrylic acid ester, polyacryloylmorpholine, polymethacryloylmorpholine, polyacrylamide, and polymethacrylamide. Is preferable.

The base resin is preferably composed of at least one material selected from the group consisting of acrylic resin, cycloolefin resin, carbonate resin, and styrene resin.
The solvent of the polymer solution preferably contains at least one alcohol.

The present invention is a method for producing a polymer-impregnated base resin, which comprises a step of impregnating a base resin with a polymer solution using a solvent having swelling property for the base resin. Therefore, since the polymer-impregnated base resin obtained by the production method is obtained by impregnating and fixing (mainly physically) the polymer in the base resin, it is possible to prevent the polymer from being washed away by washing or the like. .. Therefore, the desired performance can be maintained even if the polymer-impregnated base resin is repeatedly used. Further, since the adsorption of blood cells such as proteins and platelets can be suppressed, it is also possible to satisfactorily impart these low adsorption properties.

An example of a schematic diagram showing a process of manufacturing a polymer-impregnated base resin according to the present invention. An example of a schematic diagram of a flow path portion provided with a chamber portion in a medical inspection device.

The present invention is a method for producing a polymer-impregnated base resin (base resin impregnated with a polymer), which comprises a step of impregnating a base resin with a polymer solution using a solvent having swelling property for the base resin.

When the polymer solution using a solvent having swelling property to the base resin is impregnated into the base resin by immersion or the like, the polymer permeates into the base resin together with the solvent, and then when the solvent is removed, the polymer solution is impregnated and fixed. In addition, a polymer-impregnated base resin (mainly physically immobilized) is produced. When a body fluid such as blood or a protein is brought into contact with the polymer-impregnated base resin, the adsorption and adhesion of blood cell cells such as platelets and erythrocytes and the protein can be suppressed.

Therefore, for example, when the body fluid such as blood is in contact with the polymer-impregnated base resin and the body fluid is discharged (removed), the adsorption and adhesion of blood cells to the surface of the polymer-impregnated base resin can be sufficiently suppressed. ..

Examples of the base resin include acrylic resins (polyacrylic resins) such as methyl polyacrylic acid, methyl polymethacrylate, polyacrylic acid, and polymethacrylic acid, cycloolefin resins (polycycloolefins), carbonate resins (polycarbonates), and styrene resins. Examples thereof include polyester resins such as (polystyrene) and polyethylene terephthalate (PET), and polydimethylsiloxane.

In the present invention, a solvent having swellability to the base resin is used. In the present invention, the swellability means the property that the base resin does not dissolve at 70 ° C. or lower, but penetrates into the base resin. At this time, the volume of the base resin increases slightly due to the permeation of the solvent.

Examples of the polymer include homopolymers and copolymers of various monomers. Specific examples thereof include polyacrylic acid, polyacrylic acid ester, polymethacrylic acid, polymethacrylic acid ester, polyacryloylmorpholine, polymethacryloylmorpholine, polyacrylamide, polymethacrylamide and the like. As the polymer, a hydrophilic polymer having hydrophilicity is suitable, for example, a homopolymer and a copolymer of one or more kinds of hydrophilic monomers, one kind or two or more kinds of hydrophilic monomers, and other. Examples thereof include a copolymer with a monomer.

Specific examples of the monomer such as a hydrophilic monomer include (meth) acrylic acid, (meth) acrylic acid ester, alkoxyalkyl (meth) acrylate such as (methoxyethyl (meth) acrylate, and hydroxy such as hydroxyethyl (meth) acrylate. Alkyl (meth) acrylate), (meth) acrylamide, (meth) acrylamide derivative having a cyclic group ((meth) acryloylmorpholine, etc.), and the like can be mentioned. Of these, (meth) acrylic acid, (meth) acrylic acid ester, and (meth) acryloylmorpholine are preferable, alkoxyalkyl (meth) acrylate is more preferable, and 2-methoxyethyl acrylate is particularly preferable.

The other monomers are not particularly limited as long as they do not impair the effects of the present invention, but betaine-based monomers, deliquescent monomers and the like can be preferably used. Examples of the betaine-based monomer include carboxybetaine, sulfobetaine, and phosphobetaine. Examples of the deliquescent monomer (a monomer having a property of taking in water (water vapor) in the air and spontaneously forming an aqueous solution) include an alkali metal-containing monomer (a monomer containing an alkali metal in the molecule), and among them, 3-Sulfopropyl (meth) acrylate alkali metal salts are preferred, with 3-sulfopropyl potassium methacrylate being particularly preferred.

The solvent in the polymer solution (solution in which the polymer is dissolved in a solvent) is not particularly limited as long as it is water or an organic solvent in which the polymer can be dissolved, and alcohol (methanol, ethanol, etc.), acetone, benzene, toluene, methyl ethyl ketone, etc. Ethyl acetate, THF and the like can be mentioned. Among them, a solvent containing at least one alcohol is preferable, and examples thereof include one or more alcohol solvents, a mixed solvent of alcohol and a non-polar solvent, and the like.

In the present invention, as a solvent having swelling property for the base resin, it is preferable to use a solvent capable of swelling the base resin but not dissolving the base resin but dissolving the polymer. In this case, it is used in a harsh state as a medical / medical substrate, filter, flow path, tube, etc. (use in a fast flow field, use in a solution such as acid / alkali or alcohol (solvent in which the polymer does not dissolve, the polymer The polymer does not detach even if it is different from the solvent of the solution, or in the case of the solvent of the polymer solution, it is used at a temperature different from the impregnation temperature, etc.), or it is used repeatedly, etc.), and blood cells and proteins are adsorbed and adhered. Can be remarkably suppressed.

In the present invention, the step of impregnating the base resin with the polymer solution is performed. In the present invention, impregnation means permeating the polymer into the base resin. The impregnation method is not particularly limited as long as the polymer permeates into the base resin, and is applicable. For example, the polymer solution is applied or sprayed onto the base resin, or the base resin is put into the polymer solution. Immersion and the like.

In the present invention, the polymer is impregnated and fixed (mainly physically fixed) in the base resin by impregnating the base resin with the polymer using the polymer solution and then appropriately removing the solvent by drying or the like. A resin (polymer-impregnated base resin) can be obtained. A method of removing the solvent of the polymer solution after impregnation and then washing with the solvent used for the polymer solution, a method of further removing the unimpregnated polymer after the washing, and the like may be adopted.

FIG. 1 is an example of a schematic diagram showing a process of manufacturing a polymer-impregnated base resin by the manufacturing method of the present invention. When the base resin 11 is impregnated with a polymer solution in which the polymer 13 is dissolved in a solvent 12 having swellability to the base resin 11, the solvent 12 and the polymer 13 invade into the base resin 11. Then, when drying or the like is applied, the solvent 12 is removed, while the polymer 13 remains and is immobilized in the substrate resin 11, and the polymer 13 is immobilized in the substrate resin 11. (Film thickness 14 of the polymer impregnated layer) is produced.

The film thickness of the polymer-impregnated layer in the polymer-impregnated base resin is 2 to 200 nm, preferably 2 to 100 nm, more preferably 2 to 50 nm, and further preferably 2 to 30 nm. Within the above range, good protein and low adsorption to blood cell cells tend to be obtained.

The polymer-impregnated base resin obtained by the production method of the present invention can be applied to medical inspection devices and the like (medical and medical substrates, filters, flow paths, tubes and the like used in the medical and medical fields). For example, a medical inspection device having a flow path portion including a chamber portion and having at least a part of the flow path portion made of a polymer-impregnated base resin having a polymer-impregnated layer can be mentioned. In such an apparatus, it is possible to prevent the polymer from being washed away by washing or the like. In addition, low adsorption of blood cells such as platelets and proteins to the inner surface of the flow path can be realized.

Hereinafter, an example of the embodiment of the medical inspection device will be described with reference to the drawings.
FIG. 2 is an example of a schematic diagram of the medical inspection device 2. The medical inspection device 2 includes a flow path portion 21, and has a chamber portion 22 in the flow path portion 21. All or part of the inner surface of the flow path portion 21 is made of a polymer-impregnated base resin (not shown) having a polymer-impregnated layer. Further, it is preferable that all or part (preferably all) of the inner surface of the chamber portion 22 is made of a polymer-impregnated base resin having a polymer-impregnated layer.

Even if blood or body fluid is introduced into the flow path portion 21, adsorption of platelets, erythrocytes, etc. is suppressed. The length L21 (flow direction) of the flow path portion 21 and the width R21 (average) of the flow path portion 21 other than the chamber portion 22 may be appropriately set according to what is to be introduced. For example, R21 is preferably 0.1 to 5 mm, more preferably 0.2 to 3 mm.

The shape (three-dimensional shape, substantially two-dimensional shape (bag shape), etc.), size, etc. of the chamber portion 22 may be appropriately set according to what is to be introduced.

The medical inspection device prepares, for example, a flow path portion made of a polymer-impregnated base resin having a polymer-impregnated base resin in whole or a part of the inner surface of the flow path portion 21 shown in FIG. 2, and further required. It can be manufactured by adding other members (parts) accordingly.

Specifically, (1) a method of injecting a polymer solution using a solvent having swelling property to a base resin into the inside of the flow path portion and holding the polymer solution for a predetermined time, and (2) the polymer solution of the flow path portion. A flow path made of a polymer-impregnated base resin having a polymer-impregnated layer by impregnating all or a part of the inner surface of the flow path portion with a polymer solution by a known method such as a method of coating (spraying) the inner surface. The part is made. Then, by adding other parts to the obtained flow path portion as needed, a medical inspection device can be manufactured.

Conventionally known materials and methods can be applied to the injection method, the coating (spraying) method, and the like.
The holding time of (1) and (2) may be appropriately set depending on the size of the flow path, the type of liquid to be introduced, etc., but is preferably 5 minutes to 10 hours, more preferably 10 minutes to 5 hours. 15 minutes to 2 hours is even more preferred. After holding, the excess polymer solution may be drained and dried as appropriate.

The chamber portion of the medical inspection device may be a microchamber. In the case of a microchamber, the width of the chamber portion is preferably 20 to 200 μm, and the number of chamber portions is preferably 1 to 500,000.

In a medical inspection device, it is preferable that at least a part of the inner surface of the flow path portion has a water contact angle of 25 to 90 degrees. When it has a predetermined water contact angle, the effect of the present invention can be obtained satisfactorily.

The medical inspection device further preferably has a cell sorting filter structure, a pillar structure, or a dish structure (dish-shaped dent structure). As the filter and pillar, those known in the art can be appropriately used.

Blood or body fluid can be inspected using the polymer-impregnated base resin obtained by the production method of the present invention. Specifically, as described above, by using the medical inspection device of FIG. 2 using the polymer-impregnated base resin having the polymer-impregnated layer, adhesion / adhesion of blood cells and proteins in blood or body fluid is suppressed. can.

Hereinafter, the present invention will be specifically described based on examples, but the present invention is not limited thereto.

(Example 1)
Using AIBN (azobisisobutyronitrile), 2-methoxyethyl acrylate was thermally polymerized at 80 ° C. for 6 hours to prepare poly2-methoxyethyl acrylate (PMEA) (molecular weight Mn: about 15,000, Mw: about). 50,000).
A base material was prepared by spin-coating a toluene solution of PMMA on a silicon substrate at 3000 rpm (PMMA substrate). This substrate is immersed in a 0.5% wt methanol solution of the poly2-methoxyethyl acrylate at 23 ° C. for 2 hours, washed with methanol, vacuum dried, and a PMEA-impregnated PMMA substrate (base resin: PMMA, polymer: PMEA). )made.

( Reference example 1 )
A commercially available polyurethane sheet is immersed in a 0.5 wt% THF solution of poly2-methoxyethyl acrylate at 23 ° C. for 2 hours, washed with methanol, vacuum dried, and a PMEA-impregnated PU substrate (base resin: PU, polymer: PMEA). It was created.

(Example 3)
A commercially available PMMA substrate (thickness 1 mm) is immersed in a 2.5 wt% methanol solution of the above poly2-methoxyethyl acrylate at 23 ° C. for 2 hours, washed with methanol, vacuum dried, and polymer-impregnated commercially available PMMA substrate (base material). Resin: PMMA, polymer: MeOH) was prepared.

( Reference example 2 )
A base material was prepared by spin-coating a toluene solution of PS (polystyrene) on a silicon substrate at 3000 rpm (PS substrate). This substrate is immersed in a 0.25 wt% methanol / 1-propanol (= 50/50) solution of the above poly2-methoxyethyl acrylate at 50 ° C. for 2 hours, washed with methanol, vacuum dried, and polymer-impregnated PS substrate (PMEA impregnated PS substrate). Base resin: PS, polymer: MeOH) was prepared.

(Example 5)
A 2.5 wt% methanol solution of the above poly2-methoxyethyl acrylate was injected into a commercially available PMMA chamber (FIG. 2), immersed at 23 ° C. for 2 hours, and then the solution was sucked out with a pipette. Then, methanol was injected, sucked out, washed, and vacuum dried to prepare a PMEA-impregnated commercial PMMA chamber (base resin: PMMA, polymer: PMEA).

The length L21 and inner diameter (width) R21 of the flow path portion of the used flow path, the length L22 and inner diameter (width) R22 of the chamber portion are as follows.
L21: 60mm
R21: 1mm
L22: 42mm
R22: 9mm

(Comparative Example 1)
A substrate was prepared by simply spin-coating a toluene solution of PMMA on a silicon substrate at 3000 rpm (PMMA substrate).

(Comparative Example 2)
A commercially available polyurethane sheet was used as it was (PU substrate).

(Comparative Example 3)
A commercially available PMMA substrate (thickness 1 mm) was used as it was (commercially available PMMA substrate).

(Comparative Example 4)
A substrate was prepared by simply spin-coating a toluene solution of PS (polystyrene) on a silicon substrate at 3000 rpm (PS substrate).

The substrates and medical inspection equipment (flow path portion) produced in Examples and Comparative Examples were evaluated by the following methods.

(Film thickness of polymer impregnated layer)
The film thickness of the polymer-impregnated layer was measured (photographed) by using a TEM and measuring (photographing) a cross section of the substrate on which the polymer-impregnated layer was formed at an acceleration voltage of 15 kV and 10000 times.

(Platelet adhesion amount)
A solution prepared by mixing platelets with plasma on the surface of the substrate or inside the medical inspection device (flow path portion) prepared in Examples and Comparative Examples, and adjusting the platelet concentration (seed density) to 4 × 10 ⁷ cells / cm ² . Was dropped or injected, and allowed to stand at 37 ° C. for 1 hour. The surface or the inside was washed with phosphate buffered saline and then fixed with 1% glutaraldehyde (leave at 37 ° C. for 2 hours). Then, it was washed again with phosphate buffered saline and distilled water.
This sample was observed by SEM and the number of adsorbed platelets was counted. The number of Comparative Example 1 was set to 1, and comparisons were made by relative values.

(Water contact angle)
1 μl of distilled water was dropped on the surface of the substrate or the inner surface of the flow path, and the contact angle after 1 second was measured by the θ / 2 method (room temperature).

(Protein adsorption amount)
A solution prepared by mixing bovine serum albumin labeled with fluorescein isothiocyanate in phosphate buffered saline at 10 mg / mL was added dropwise to the substrate surface, and the mixture was allowed to stand at 37 ° C. for 1 hour. The surface was washed twice with phosphate buffered saline.
This sample was observed with a fluorescence microscope, and the fluorescence intensity at 535 nm was measured. The number of Comparative Example 1 was set to 1, and the comparison was performed with relative values. The smaller the number, the smaller the amount of protein adsorbed.

On the substrate surface of the example having the polymer-impregnated layer, both the platelet adhesion amount and the protein adsorption amount were smaller than those of the comparative example, and a low platelet adsorption amount and a low protein adsorption amount were obtained.

Similar effects can be obtained even when a hydrophilic polymer other than poly2-methoxyethyl acrylate is used.

11 Base resin 12 Swellable solvent for base resin 13 Polymer 14 Thickness of polymer impregnated layer 2 Medical inspection device 21 Channel 22 Chamber L21 Chamber length L22 Chamber length R21 Chamber Width of the flow path portion 21 other than the portion R22 Width of the chamber portion

Claims (8)

A step of impregnating the base resin with a polymer solution using a solvent having swelling property for the base resin, and a step of impregnating the base resin.
A method for producing a polymer-impregnated base resin, which comprises a step of washing with a solvent of the same type as the solvent used for the polymer solution. The polymer is at least one selected from the group consisting of polyacrylic acid, polyacrylic acid ester, polymethacrylic acid, polymethacrylic acid ester, polyacryloylmorpholin, polymethacryloylmorpholin, polyacrylamide, and polymethacrylamide. 1. The method for producing a polymer-impregnated base resin according to 1. The polymer-impregnated group according to claim 1 or 2, wherein the base resin is composed of at least one material selected from the group consisting of an acrylic resin, a cycloolefin resin, a carbonate resin, a styrene resin, and a polyurethane resin. Material resin manufacturing method. The method for producing a polymer-impregnated base resin according to any one of claims 1 to 3, wherein the solvent of the polymer solution contains at least one alcohol. The method for producing a polymer-impregnated base resin according to any one of claims 1 to 4, wherein the film thickness of the polymer-impregnated base resin in the polymer-impregnated base resin is 2 to 50 nm. A step of impregnating the base resin with a polymer solution using a solvent having swelling property for the base resin, and a step of impregnating the base resin.
Including the step of washing with the same solvent as the solvent used for the polymer solution.
The base resin is composed of at least one material selected from the group consisting of acrylic resin, cycloolefin resin, carbonate resin, styrene resin, and polyurethane resin.
The polymer is poly2-methoxyethyl acrylate,
A method for producing a polymer-impregnated base resin, wherein the polymer-impregnated layer has a film thickness of 2 to 50 nm. The polymer solution contains a methanol / 1-propanol mixed solvent and contains.
The method for producing a polymer-impregnated base resin according to claim 6, wherein the base resin is composed of a styrene resin. The polymer solution contains a THF solvent and
The method for producing a polymer-impregnated base resin according to claim 6, wherein the base resin is composed of a polyurethane resin.

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